With the continuous occurrence of drug resistance in melanoma, combination therapy of multi-targets drug has become the main development direction of targeted therapy. NRAS gene mutation is a common type of genetic variation in patients with skin malignant melanoma, which accounts for about 20%. The patients with NRAS gene mutation have poorer prognosis and specific targeted therapy drugs are lacked. Research shows that in the NRAS mutated melanoma cells, the MAPK signal pathway is activated abnormally, and there are much cell cycle checkpoint disorders. Therefore, it may have a synergistic anti-tumor effect and enhance the anti-tumor effect when inhibiting MAPK Signal Pathway Key molecule MEK and the cell cycle key regulation kinase CDK4/6 at the same time.
Novartis announced the Phase I clinical data of treating the NRAS mutated melanoma with combination therapy of the CDK inhibitor LEE011 (Ribociclib) and the MEK inhibitor MEK162 (Binimetinib) and the data showed a good clinical effect. At present, Phase II clinical trial for this combination is ongoing.
LEE011 is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitors which is for the treatment of drug-resistant breast cancer and melanoma. It has a good performance in clinical study and has received positive clinical results. Currently it is in phase III clinical studies. The chemical name of LEE011 is 7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo [2, 3-D]pyrimidine-6-carboxylic acid dimethylamide, and the structure is shown as formula (Ia):

MEK162 is an oral mitogen-activated protein kinase (MEK) inhibitor and is currently in Phase III clinical trials in the United States for the treatment of NRAS mutated melanoma, BRAF mutated melanoma and recurrent low-level plasma ovarian cancer. The chemical name of MEK162 is 5-[(4-bromo-2-fluorophenyl) amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazol-6-carboxamide, and the structure is shown as formula (Ib):

WO2014097125A1 discloses the combination of LEE011 and MEK162, but the combination is a physical mixture of the two components and the two components do not form a co-crystal which is essentially different from the present disclosure.
Pharmaceutical co-crystal is a co-crystal structure comprising two components. The interaction between the two components is generally non-covalent interactions (such as hydrogen bonding, π-π interactions, halogen bonding, etc.). The formation of the pharmaceutical co-crystal generally does not destroy the covalent bonding of active pharmaceutical ingredient. There are reports show that through forming a co-crystal the drug has the opportunity to improve the crystallization properties and physicochemical properties such as bioavailability (Pharmaceut. Res. 23(8), 2006, pp. 1888-1897.), stability and processibility (Int. J. Pham. 320, 2006, pp. 114-123.). Therefore, Pharmaceutical co-crystal is a new choice for the solid pharmaceutical preparations.
In prior art, the pharmaceutical co-crystal is usually formed of active pharmaceutical ingredient and co-crystal former, and the active pharmaceutical ingredient is usually a good donor or a receptor compound that has more rigid structure, higher symmetry, lower molecular weight and contains protons. While the co-crystal reagents are mostly pharmaceutical excipients, vitamins, amino acids and food additives. Currently, no research has reported about the co-crystals of the two drugs and their therapeutic effect, particularly there is no report about co-crystal of the two active pharmaceutical ingredients of LEE011 and MEK162.